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Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis
Abstract:
A remarkable pathological difference between grey matter lesions (GML) and white matter lesions (WML) in Multiple Sclerosis (MS) patients is the paucity of infiltrating leukocytes in GML. To better understand these pathological differences, we hypothesize that the chemokine monocyte chemotactic protein-1 (MCP-1 or CCL2), of importance for leukocyte migration, and its receptor CCR2 are more abundantly expressed in WML than in GML of MS patients. To this end, we analyzed CCL2 and CCR2 expression in the hippocampus, comprising WML and GML,of post-mortem MS patients, and of control subjects. CCL2 and CCR2 mRNA were significantly increased in demyelinated MS hippocampus. Semi-quantification of CCL2 and CCR2 immunoreactivity showed that CCL2 is present in astrocytes only in active WML. CCR2 is upregulated in monocytes/macrophages or amoeboid microglia in active WML, and in ramified microglia in active GML, although to a lesser extent. As a follow-up, we observed a significantly increased CCL2 production by WM-, but not GM-derived astrocytes upon stimulation with bz-ATP in vitro. Finally, upon CCL2 stimulation, GM-derived microglia significantly increased their proliferation rate. We conclude that within hippocampal lesions, CCL2 expression is mainly restricted to WML, whereas the receptor CCR2 is upregulated in both WML and GML. The relative absence of CCL2 in GML may explain the lack of infiltrating immune cells in this type of lesions. We propose that the divergent expression of CCL2 and CCR2 in WML and GML explains or contributes to the differences in WML and GML formation in MS.
Insights
In Multiple Sclerosis (MS), the chemokine monocyte chemotactic protein-1 (CCL2) is mainly in white matter lesions (WML), not grey matter lesions (GML). This difference in CCL2 and its receptor CCR2 may explain varied lesion formation in MS.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Multiple Sclerosis (MS) exhibits distinct pathological features between grey matter lesions (GML) and white matter lesions (WML), notably differing in leukocyte infiltration.
- Monocyte chemotactic protein-1 (MCP-1 or CCL2) and its receptor CCR2 are crucial for leukocyte migration and are investigated for their differential roles in MS lesion types.
Purpose of the Study:
- To investigate the hypothesis that CCL2 and CCR2 are more abundant in WML than GML in the MS hippocampus.
- To elucidate the role of CCL2 and CCR2 in the differential pathogenesis of GML and WML in Multiple Sclerosis.
Main Methods:
- Analysis of CCL2 and CCR2 mRNA and protein expression in post-mortem MS and control hippocampi.
- Immunohistochemical assessment of CCL2 and CCR2 in active WML and GML.
- In vitro studies assessing CCL2 production by astrocytes and microglial proliferation in response to CCL2.
Main Results:
- CCL2 and CCR2 mRNA levels were significantly elevated in demyelinated MS hippocampi.
- CCL2 immunoreactivity was primarily observed in astrocytes within active WML, while CCR2 was upregulated in monocytes/macrophages and microglia in active WML and GML.
- In vitro, WM-derived astrocytes produced more CCL2, and GM-derived microglia showed increased proliferation upon CCL2 stimulation.
Conclusions:
- CCL2 expression is predominantly localized to WML in the MS hippocampus, whereas CCR2 is upregulated in both WML and GML.
- The restricted CCL2 expression in GML may account for the reduced immune cell infiltration observed in this lesion type.
- Differential expression of CCL2 and CCR2 in WML and GML likely contributes to the distinct formation and characteristics of these lesions in Multiple Sclerosis.
